Naunyn-schmiedebergs Archives of Pharmacology最新文献

Lung cancer is the most common cause of cancer-related mortality, chemo-resistance, and toxicity limit treatment. The focus is on innovative combined phytotherapy to improve treatment outcomes. Our aim was to investigate the potential effects of daidzein nanosuspension (DZ-NS) and its combination with cisplatin (CIS) on A549 non-small lung cancer cells. Cytotoxicity was investigated using MTT and Chou-Talalay methods. Oxidative, apoptotic, and inflammatory markers were analyzed by ELISA and qRT-PCR. The IC50 value for DZ-NS was 25.23 µM for 24 h and was lower than pure DZ (IC50 = 835 µM for pure DZ). DZ-NS (at IC50x2 and IC50 values) showed synergistic cytotoxicity with CIS. The cells treated with DZ-NS had low TOS and OSI levels. However, DZ-NS failed to regulate Cas3 and TGF-β1 activation in A549 cells. MMP-9 gene expression was significantly suppressed in DZ-NS-treated cells, especially in combination therapy. DZ represents a potential combination option for the treatment of lung cancer, and its poor toxicokinetic properties limit its clinical use. To overcome these limitations, the effects of the nanosuspension formulation were tested. DZ-NS showed a cytotoxic effect on A549 cells and optimized the therapeutic effect of CIS. This in vitro synergistic effect was mediated by suppression of MMP-9 and not by oxidative stress or Cas3-activated apoptosis. This study provides the basis for an in vivo and clinical trial of DZ-NS with concurrent chemotherapy.

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Abstract

Impaired insulin and growth factor functions are thought to drive many alterations in neurodegenerative diseases like dementia and seem to contribute to oxidative stress and inflammatory responses. Recent studies revealed that nasal growth factor therapy could induce neuronal and oligodendroglia protection in rodent brain damage induction models. Impairment of several growth factors signaling was reported in neurodegenerative diseases. So, in the present study, we examined the effects of intranasal co-treatment of insulin and a pool of growth factor-rich serum (GFRS) which separated from activated platelets on memory, and behavioral defects induced by intracerebroventricular streptozotocin (icv-STZ) rat model also investigated changes in the hippocampal oxidative-nitrosative state and histology. We found that icv-STZ injection (3 mg/kg bilaterally) impairs spatial learning and memory in Morris Water Maze, leads to anxiogenic-like behavior in the open field arena, and induces oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia death in the hippocampus. GFRS (1µl/kg, each other day, 9 doses) and regular insulin (4 U/40 µl, daily, 18 doses) treatments improved learning, memory, and anxiogenic behaviors. The present study showed that co-treatment (GFRS + insulin with respective dose) has more robust protection against hippocampal oxidative-nitrosative stress, neuroinflammation, and neuronal/oligodendroglia survival in comparison with the single therapy. Memory and behavioral improvements in the co-treatment of insulin and GFRS could be attributed to their effects on neuronal/oligodendroglia survival and reduction of neuroinflammation in the hippocampus.

Abstract

The aim of the research was to evaluate the influence of antagonists of specific beta-adrenergic receptor subtypes on bowel motility following abdominal surgery in rat model of postoperative ileus. Bowel motility was measured by the intestinal transit of Evans blue introduced via orogastric tube after surgical procedures of skin incision, laparotomy and laparotomy with gut manipulation. Male rats were given individual adrenergic receptor subtypes antagonists intraperitoneally, and the influence of administered agents on intestinal transit of Evans blue was then evaluated. No statistically significant differences in the length of intestine in tested rats were observed. Propranolol administered prior to surgical procedure has shown protective effect on Evans blue migration in rats undergoing laparotomy and gut manipulation. Intestinal dye transit for propranolol doses of 10, 30 and 45 mg/kg was 18.00 ± 1.88c m, 23.75 ± 1.71 cm and 22.5 ± 2.43 cm, respectively, and for last two doses, statistically significant increase of dye passage was noted, compared to Evans blue transit of 11.00 ± 2.43 cm in the control group. No acceleration of dye migration was seen following administration of beta1-, beta2- and beta3-selective adrenergic receptor antagonist metoprolol, ICI 118.551 and SR58894A, respectively. Our research confirmed that propranolol at high doses, as seen by other researchers, improved bowel motility in early phase of postoperative ileus. That slight acceleration of intestinal dye transit after surgery with gut manipulation is rather connected with membrane-stabilizing action, than the receptor blocking effect, as this effect was not observed after the application of selective antagonists of respective subtypes of beta-adrenergic receptor.

To explore the regulatory effect of human epididymis protein 4 (HE4) on renal fibrosis in mice with lupus nephritis (LN) and the underlying mechanism. Ten-week old MRL/LPR mice were injected with HE4 shRNA adenovirus vector through the renal pelvis for 5 days. Renal tissues were extracted for HE and Masson staining to evaluate pathological changes and fibrosis in lupus nephritis mice. The level of urine protein was measured using a biochemical analyzer, while the expression level of HE4 and p-NF-κB p65 in renal tissues was visualized using an immunofluorescence assay. The level of β2-microglobulin (β2-MG), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (Kim-1) was determined by the immunohistochemical assay. Western blotting was used to determine the levels of C3, HE4, matrix metalloproteinase-2 (MMP2), MMP9, p-p65, prss23, and prss35 in renal tissues. Compared to wild-type C57BL/6 mice, MRL/LPR mice showed a marked increase in the number of glomeruli, hyperplasic basement membrane, severe infiltration of inflammatory cells in renal tubules and glomeruli, obvious necrosis in glomeruli, elevated fibrosis levels, and increased levels of urine protein, β2-MG, NGAL, Kim-1, C3, HE4, MMP2, MMP9, and p-p65; and decreased levels of prss23 and prss35 were observed in MRL/LPR mice. After the administration of the HE4 shRNA adenovirus vector, the repaired structure of renal tubules and glomeruli improved infiltration of inflammatory cells, reduced collagen fiber and urine protein, suppressed levels of C3, HE4, MMP2, MMP9, and p-P65, and facilitated the expression of prss23 and prss35 which were observed. Silencing HE4 improved renal fibrosis and inhibited inflammation in mice with lupus nephritis, which may play a role in inhibiting C3/MMPs and promoting prss-related protein expression.

Apigenin (APG) is a plant-based flavonoid that possesses antioxidants, anti-inflammatory, and modulates P38 MAPK as well as tyrosinase. Hydroquinone (HQ), a phenolic compound was used to induce vitiligo in C57BL/6 mice. The present study was performed to check the therapeutic potential of apigenin in HQ-induced vitiligo via targeting P38 MAPK pathway. In the present study, 41 C57BL/6 mice were divided into six groups containing seven animals per group except normal group. (I) normal group, (II) HQ group, (III) to (IV) APG with (1%, 2.5%, 5%), and (VI) tacrolimus (TAC) group. Topical application of HQ was performed from day 1 to day 20 to, (II), (III) to (IV) APG with (1%, 2.5%, 5%), (VI) tacrolimus (TAC) group, and then APG; tacrolimus (TAC) was applied from day 21 to day 60 after removing the hair. In the case of (I) normal group and (II) HQ group, we smeared them with water for 60 days and HQ for 20 days in their individual group. On day 61 after anesthesia, a part of the target skin was peeled and blood serum was taken to check the level of malondialdehyde, cholinesterase, catalase, tyrosinase, pro-inflammatory cytokines, and expression of P38 MAPK, histology of melanin containing hair follicles and depigmentation evaluation. Applying HQ topically had a noticeable impact on depigmentation, inflammatory indicators, oxidative stress, and lowered tyrosinase activity. Further HQ reduced melanin containing hair follicles and increased expression of P38 MAPK was confirmed by histopathology and immunohistochemistry. Furthermore, application of APG and TAC after day 21 to 60 significantly reduced depigmentation, inflammatory markers, oxidative stress, and increased tyrosinase. Furthermore, APG increased melanin containing hair follicles and decreased expression of non-phosphorylated P38 MAPK, as confirmed by histopathology and immunohistochemistry. Our finding demonstrated that APG significantly prevented HQ-induced vitiligo by acting as an anti-inflammatory, increasing tyrosine, and reducing the expression of non-phosphorylated P38 MAPK.

Ischemic heart diseases such as myocardial infarction (MI) are a global health problem and a leading cause of mortality worldwide. Angiogenesis is an important approach for myocardial healing following ischemia. Thus, this study aimed to explore the potential cardiac angiogenic effects of selenium (Se), alone and in combination with the tumor necrosis factor-alpha inhibitor, pentoxifylline (PTXF), via Akt/HIF-1α signaling. MI was induced in rats using two subcutaneous doses of isoprenaline (ISP) at a 24-h interval (150 mg/kg). One week later, rats were orally given Se (150 µg/kg/day), PTXF (50 mg/kg/day), or Se/PTXF combination. ISP-induced myocardial damage was evident by increased HW/TL ratios, ST segment elevation, and increased serum levels of CK-MB, LDH, and troponin-I. ISP increased the cardiac levels of the lipid peroxidation marker MDA; the pro-inflammatory cytokines IL-6, IL-1β, and TNF-α; and the pro-apoptotic protein Bax and caspase-3. In contrast, the cardiac levels of the antioxidant markers GSH and SOD and the anti-apoptotic marker Bcl-2 were reduced. Furthermore, ISP markedly increased the cardiac levels of p-Akt and HIF-1α proteins and the cardiac gene expression of ANGPT-1, VEGF, and FGF-2. Treatment with Se both alone and in combination with PTXF ameliorated the ISP-induced myocardial damage and further increased cardiac angiogenesis via Akt/HIF-1α signaling. Se/PTXF combined therapy was more beneficial than individual treatments. Our study revealed for the first time the cardiac angiogenic effects of Se both alone and in combination with PTXF in myocardial infarction, suggesting that both may be promising candidates for clinical studies.

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Cyfluthrin, a widely used synthetic pyrethroid insecticide, poses potential risks to both human health and the environment due to its extensive application in residential, agricultural, and outdoor settings. Conversely, benfotiamine, a fat-soluble derivative of vitamin B1, offers versatile therapeutic potential. This experimental study aimed to investigate the impact of cyfluthrin exposure during the prepubertal period on sperm characteristics and testicular tissue integrity in male rats, as well as to assess the protective effects of benfotiamine. A total of 32 4-week-old Wistar albino male rats were divided into four groups. Group I received daily oral gavage of 1 ml/kg/day of olive oil (control). Group II was administered cyfluthrin (54 mg/kg/day) dissolved in 1 ml of olive oil. Group III received both cyfluthrin (54 mg/kg/day) and benfotiamine (100 mg/kg/day) in olive oil. Group IV was given benfotiamine (100 mg/kg/day) in olive oil. After 5 weeks of treatment, the rats underwent evaluations for sperm motility, epididymal sperm density, and abnormal sperm rates. Additionally, their testicular tissues were examined histologically and immunohistochemically. This study underscores the potential hazards of cyfluthrin exposure on male reproductive health and highlights the protective role of benfotiamine in mitigating these effects. It emphasizes the importance of careful pesticide usage and dosage considerations to prevent potential public health issues, including infertility, associated with long-term exposure to pesticides like cyfluthrin.

An imbalance in coagulation is associated with cardiovascular events. For prevention and treatment, anticoagulants, currently mainly xabans and gatrans, are used. The purpose of the present study was to provide a head-to-head comparison since there are no studies directly evaluating these novel anticoagulants. An additional aim was to find whether selected anthropological and biochemical factors can affect their anticoagulant properties as they are used in fixed doses. In this cross-sectional study, blood from 50 generally healthy donors was collected, and coagulation responses to dabigatran, argatroban, rivaroxaban, and apixaban, at a concentration of 1 μM, were analyzed. Heparin was used as a positive control. Prothrombin time (PT) expressed as international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were measured and compared. Rivaroxaban was the most active according to PT/INR while argatroban according to aPTT. The ex vivo anticoagulant effect measured by INR correlated inversely with body mass index (BMI) in all four anticoagulants tested. Shortening of aPTT was associated with higher cholesterol and triglyceride levels. No sex-related differences were observed in response to the anticoagulant treatments. As this was an ex vivo study and pharmacokinetic factors were not included, the influence of BMI is of high therapeutic importance.

Abstract

Breast cancer and osteosarcoma are common cancers in women and children, respectively, but ideal drugs for treating patients with breast cancer or osteosarcoma remain to be found. Micafungin is an antifungal drug with antitumor activity on leukemia. Based on the notion of drug repurposing, this study aims to evaluate the antitumor effects of micafungin on breast cancer and osteosarcoma in vitro and in vivo, and to elucidate the underlying mechanisms. Five breast cancer cell lines (MDA-MB-231, BT-549, SK-BR-3, MCF-7, and 4T1) and one osteosarcoma cell line (143B) were chosen for the in vitro studies. Micafungin exerted an inhibitory effect on the viability of all cell lines, and MCF-7 cells were most sensitive to micafungin among the breast cancer cell lines. In addition, micafungin showed an inhibitory effect on the proliferation, clone formation, and migration in MCF7 and 143B cells. The inhibitory effect of micafungin on the growth of breast cancer and osteosarcoma was further confirmed with xenograft tumor mouse models. To explore the underlying mechanisms, the effect of micafungin on epithelial-mesenchymal transition (EMT) was examined. As expected, the levels of matrix metalloproteinase 9 and vimentin in MCF-7 and 143B cells were notably reduced in the presence of micafungin, concomitant with the decreased levels of ubiquitin-specific protease 7 (USP7), p-AKT, and p-GSK-3β. Based on these observations, we conclude that micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in an USP7/AKT/GSK-3β pathway-dependent manner.

An anticancer agent derived from a natural product, parthenolide (PN), was studied to formulate PN into poly(lactic-co-glycolic acid) (PLGA). Polydopamine (PDA) was employed to modify the surface of PN-PLGA. Following characterization, the PN-PLGA-PDA was evaluated for its in vitro release, cytotoxicity, and ability to induce apoptosis using flow cytometry and real-time quantitative PCR. According to the present study, PN-PLGA-PDA had a size of 195.5 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. The SEM results confirmed the size and spherical shape of the nanoparticles. The percentage of encapsulation efficiency was 96.9%. The zeta potential of PN-PLGA-PDA was − 31.8 mV which was suitable for its stability. FTIR spectra of the PN-PLGA-PDA indicated the chemical stability of the PN due to intermolecular hydrogen bonds between polymer and drug. The release of PN from PN-PLGA-PDA in PBS (pH 7.4) was only 20% during the first 48 h and less than 40% during 144 h. PN-PLGA-PDA exhibited anticancer properties in a dose-dependent manner that was more cytotoxic against cancer cells than normal cells. Moreover, real-time qPCR results indicated that the formulation activated apoptosis genes to exert its cytotoxic effect and activate the NF-kB pathway. Based on our findings, PN-PLGA-PDA could serve as a potential treatment for cancer.